Ecological study of ambient air pollution exposure and mortality of cardiovascular diseases in elderly

As an independent risk factor, ambient air pollution can assume a considerable part in mortality and worsening of cardiovascular disease. We sought to investigate the association between long-term exposure to ambient air pollution and cardiovascular disease mortality and their risk factors in Iranian's elderly population. This inquiry was conducted ecologically utilizing recorded data on cardiovascular disease mortality from 1990 to 2019 for males and females aged 50 years or more from the Global Burden of Disease dataset. Data was interned into Joinpoint software 4.9.0.0 to present Annual Percent Change (APC), Average Annual Percent Change (AAPC), and its confidence intervals. The relationship between recorded data on ambient air pollution and cardiovascular disease' mortality, the prevalence of high systolic blood pressure, high LDL cholesterol levels, high body mass index, and diabetes mellitus type2 was investigated using the Spearman correlation test in R 3.5.0 software. Our finding demonstrated that cardiovascular diseases in elderly males and females in Iran had a general decreasing trend (AAPC = −0.77% and −0.65%, respectively). The results showed a positive correlation between exposure to ambient ozone pollution (p ≤ 0.001, r = 0.94) ambient particulate and air pollution (p < 0.001, r = 0.99) and mortality of cardiovascular disease. Also, ambient air pollution was positively correlated with high systolic blood pressure (p < 0.001, r = 0.98), high LDL cholesterol levels (p < 0.001, r = 0.97), high body mass index (p < 0.001, r = 0.91), diabetes mellitus type2 (p < 0.001, r = 0.77). Evidence from this study indicated that ambient air pollution, directly and indirectly, affects cardiovascular disease mortality in two ways by increasing the prevalence of some traditional cardiovascular disease risk factors. Evidence-based clinical and public health methodologies are necessary to decrease the burden of death and disability associated with cardiovascular disease.


Scientific Reports
| (2022) 12:21295 | https://doi.org/10.1038/s41598-022-24653-0 www.nature.com/scientificreports/ Iran's aging population will be forecasted to be 10.5% in 2025 and 21.7% in 2050, following the oldest population in the region by 2050 17 . Despite the medical advances in treatment and control of CVD, which have prompted a significant decrease in CVD rate, prevention is still considered a priority, especially to reduce clinical expenses 18,19 . Due to the vulnerability of the cardiovascular system to environmental factors reported in previous studies in other earas 20,21 , this ecological research was performed aimed to analyze 1-the relationship between AAP exposure and CVD mortality as the first cause of death in Iran, 2-the relationship between exposure to AAP and the prevalence of traditional risk factors for CVD, including diabetes, hypertension, obesity, and high LDL cholesterol in Iranian over 50 years of age in 1990-2019.

Materials and methods
Data collection. Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. Data on CVD mortality was collected separately for each year from 1990 to 2019 in Iran based on sex and age groups of 50-69 years and over 70 years 22,23 . In addition, the prevalence of traditional CVD risk factors collected by year and in the age and sex groups of 50-69 years and over 70 years, tobacco use, smoking, diabetes mellitus type 2 (DM2), high LDL cholesterol, high body mass index (BMI), and high systolic blood pressure (SBP). The definition of the elderly group with a reference for considering 50 years old as a cut point of age for the elderly group was considered.
The blood low-density lipoprotein (LDL) concentration is estimated in mmol/L, and the theoretical minimum risk exposure level value (TMREL) is used with a uniform distribution between 0.7 and 1.3 mmol/L. The values of brachial SBP are estimated in millimeters of mercury, and TMREL SBP 110 to 115 mm of mercury is used. DM is characterized collectively as a metabolic disease whose common component is a raised blood glucose level (hyperglycemia). Also, adults' high BMI (ages 20 and up) is characterized as a BMI of more than 20-25 kg body weight in the second power of height (meters) 22 . Air pollution exposure in this study is defined as ambient particulate air pollution (PM), ambient ozone pollution, and air pollution (the sum of PM and ozone pollution) based on the Global Burden of Disease (GBD) categorization in micrograms per cubic meter (µg/m 3 ). Satellite data has been used to measure air pollution 22 .
GBD dataset uses many different sources to populate the information in the GHDx. Most information about datasets and series comes from the data providers; also was used many of the resources are noted on the Data Sites We Love page, particularly are indebted to organizations such as IPUMS, ICPSR, and the World Bank. For older data, WorldCat is an invaluable resource. All of the data is collected from the following official websites: http:// www. healt hdata. org/.
Based on the GBD 2019 study, this site covers injuries and risk factors from 1990 to 2019, covering 204 countries and territories. In total, 369 causes of illness and injury were systematically analyzed. The methodology of the GBD studies and the principal changes incorporated into the GBD 2019 method has been explained in detail elsewhere 24 . Statistical analysis. Excel software was used for preliminary analysis, including graphs and maps. Then the information was prepared to enter the joinpoint software. Descriptive analysis for CVD mortality was performed using the regression model in the Joinpoint software (version 4.9.0.0). The joinpoint software is one of the statistical software available by the American Cancer Society to perform joinpoint regression. The latest version of the software was used to perform the regression analysis of attachment points. The regression of attached points actually forms segments by creating statistically significant points compared to the previous point, and for each segment or piece, an APC (annual percentage change) or annual percentage change will be created. In addition, the software provides average annual percentage change or AAPC (Average Annual percentage change). With these two values, the trend of changes from 1990 to 2019 was investigated. We reported the APC, AAPC, and related confidence intervals in the Iranian male and female populations over 50 years old separately. The Descriptive results of the PM data section, the mortality data related to ambient particulate matter pollution exposure, particulate matter pollution exposure, and air pollution exposure are reported separately in the method section of the jointpoint regression model as well as deathes due to the CVD. Spearman's correlation was utilized to investigate the relationships between ambient air pollution data and specific CVD mortality rates and the prevalence of high SBP, high BMI, DM2, high LDL cholesterol, and other risk factors in the R software (version 3.5.0).
Correlations of air pollution-related mortality or prevalences for each corresponding year are analyzed. All statistical analyses were two-sided, and a p-value less than 0.05 (p < 0.05) was considered significant. Correlation intensity was interpreted based on correlation values; r = 0.8-1 very strong correlation, r = 0.6-0.08 strong correlation, r = 0.4-0.6 moderate correlation, r = 0.2-0.4 low or weak correlation relationship 25 . The detail of the plan of the study was shown in the Fig. 1.

Results and discussion
One of the most controversial issues related to climate is urban development and its pollution. Researches on air pollutants and climatic elements suggest a link between the two factors and the mortality and incidence of disease. The extent to which the climate effect the severity of many diseases, including lung, heart, infectious and contagious diseases, is undeniable 26 . Cardiovascular failure is a major general health problem that influences over 23 million people worldwide, with a 1-year mortality rate of 30% and a rate of annual hospitalization of 2%. Recently, AAP has been considered a short-term trigger in developing heart failure [27][28][29][30] . The present study uses recorded data on mortality of the CVD and risk factors for this disease (DM2, high LDL cholesterol, high BMI, and high SBP) in age groups above 50 years and its relationship with recorded data from air pollution from 1990 to 2019.  Table 1). The latest GBD study estimates that in 2019, there were 8.76 million disability-adjusted life years (DALYs, 146,000 deaths among females, and 131,000 deaths among males due to cardiovascular and circulatory diseases 31 . Descriptive results of PM data. Descriptive results of mortality data data on ambient particulate matter exposure, particulate matter pollution, ambient ozone exposure, and air pollution exposure from 1990 to 2019 in over 50 years males and females were shown in Figs. 5, 6, 7 and 8, respectively. www.nature.com/scientificreports/ These results showed that mortality due to exposure to ambient particulate matter pollution in females over 50 years had an uptrend trend [AAPC = 0.85% (CI: 0.7 to 1.01), respectively] and also had an ascending direction in males over 50 years [AAPC = 0.37% (CI: 0.23 to 0.50), respectively] (see in Table 2).
Finally, the mortality resulting from exposure to air pollution in males over 50 years had a downward trend [AAPC = −0.18% (CI: −0.4 to 0.04), respectively] and had a uptrend in females over 50 years [AAPC = 0.13% (CI: 0.0 to −0.26), respectively] (see in Table 5).    www.nature.com/scientificreports/ Recently, air pollution has become a significant phenomenon, especially in developing countries, due to the increase of vehicles, congested traffic, inappropriate control of the release of pollutants from the resources, industrialization, and improper laws 32,33 . So, in this situation, air pollution has an increasing trend 34 . Particulate matter (PM), which was emitted due to biogenic and anthropogenic sources and produced by atmospheric reactions, is deliberated as the averse airborne pollutants 35 . Currently, West Asia is affected by dust storms in deserts, raising    41 . There is a significant relation between dust events and daily hospitals because of respiratory illnesses in Asia [42][43][44] . Epidemiological inquiries have illustrated the      45,46 . Moreover, PM exposure has caused oxidative stress and systemic inflammation, as mentioned in some research 47,48 . Therefore there is an authoritative relationship between ambient exposure to air pollution and cardiopulmonary morbidity and mortality 48,49 .
Ambient air pollution exposure and CVD mortality. The relationship between CVD mortality and AAP levels is shown in Fig. 9. There was significant relationship and positive correlation between CVD mortality and ambient PM (p ≤ 0.001, r = 0.99), ambient ozone pollution (p ≤ 0.001, r = 0.94), and ambient air pollution (p ≤ 0.001, r = 0.99) in over 50 years adults in Iran. Brook et al. 's research estimated that 69% of early deaths result in CVD, comprising ischemic heart disease and stroke, while lung disease accounts for only 28% 7 . Evaluations in the GBD Scheme showed that AAP greatly affects mortality more than any other important modifiable factor, including low physical activity and elevated cholesterol and sodium diets 50 . Numerous manifestations of CVD are related to air pollution, including arterial and venous circulation. Air pollution exposure additionally appears to assume a significant part in disease progression. Incredibly, there is ample evidence of PM's adverse effects on cardiovascular health compared to gaseous pollutants 51 . Significant effects of PM 2.5 were obtained from long-term exposure that affects mortality from CVD 52 . The risk of CVD following exposure to PM2.5 was higher in men, the elderly, and those with hypertension, diabetes, heart disease, or background of stroke 53 . Findings of the Thurston et al. study reported that PM2.5 exposure for a long course increases total risk and CVD risk in this cohort of subjects 54 . Some studies mention the rapid effect of exposure to air pollutants on the cardiovascular system 53,55,56 . The apparent link between air pollution and cardiovascular failure's systematic review and meta-analysis demonstrated that the transient rise in gas and particulate components was positively associated with hospitalization risk or death from congestive heart failure. People with persistent heart failure, hypertension, and arrhythmias are at a higher risk 5 . Several links have recently been recorded between out-of-hospital cardiac arrest and air pollution, mainly PM and ozone 57 .
Air pollution with directly and/or indirectly biological pathways affects CVD. Direct impacts of air pollution give a conceivable clarification to the event of fast cardiovascular reactions. For example, gases with PM 2.5 soluble substances directly pass through the pulmonary epithelium into the bloodstream 58 and raise the risk of ventricular fibrillation, myocardial infarction, and cardiac arrest by having a direct but weak effect on ventricular arrhythmogenesis 59 . PM 2.5, due to its small size, allows reaching the airways and small alveoli. Studies have shown that short-term exposure to PM boosts the rate of proinflammatory mediators in the blood, coagulation, and inhibition of fibrinolytic capacity 60,61 . Diesel exhaust exposure also causes inflammation within the plaque, changes in vasomotor tone, and inflammatory mediators 62 .
Among several metabolisms associated with air pollution and CVD mortality, the significant paths are induction of oxidative stress, systemic inflammation, endothelial function, atherosclerotic function, and CVD's risk assessment in an individual is usually conducted by CVD's traditional risk factors and subsequently anticipated using fully accessible algorithms, such as the Framingham Risk Score (FRS) 70 . Some of the most common metabolic consequences of fat, such as high blood pressure, diabetes mellitus, dyslipidemia, and obesity, were considered the principal risk factors for CVD (Bays et al., 2021). Also, In past texts, it has been well established that smoking and physical inactivity are among the risk factors for CVD [71][72][73][74] .
It remains to be seen, despite the widespread exposure to AAP and the relationship between AAP and traditional CVD risk factors, How important is this exposure to ambient air pollution on the prevalence, exacerbation, and mortality of CVD directly or indirectly? Ambient air pollution exposure and the prevalence of CVD risk factors. The relationship between the prevalence of CVD risk factors in the population over 50 years, including DM2, high SBP, high BMI, high LDL cholesterol, and AAP, was shown in Fig. 11. Analysis Spearman correlation displayed a significant relationship and positive correlation between air pollution and high SBP (p ≤ 0.001, r = 0.89), high LDL cholesterol (p ≤ 0.001, r = 0.87), high BMI (p ≤ 0.001, r = 0.83) and DM2 (p ≤ 0.001, r = 0.77).
There is a reciprocation interaction between air pollution and risk factors of CVD. Simultaneously, air pollutants may exacerbate and constantly stimulate several traditional risk factors 75,76 . All of which increase the incidence and severity of CVD. Hypertension is a complex disease with unknown causes. The positive relation between hypertension and CVD has been well demonstrated in some potential cohort research in developed and www.nature.com/scientificreports/ developing countries [77][78][79] . It influences almost one billion people worldwide and participates significantly in GBD and mortality 80 . Over recent years, human epidemiological investigations have assessed the relationship between long-term and short-term exposure to air pollution with hypertension and BP levels 81,82 . Exposure to AAP and potential environmental pollutants, including heavy metals, are associated with the prevalence of hypertension 83 . Numerous panel studies worldwide have also shown an association between concentrations of PM 2.5 , carbon black, and other pollutants with increased BP from a few hours to a couple of days 84,85 . Perhaps most important is prolonged exposure to PM 2.5 and traffic-related emissions, which may increase chronic hypertension by themselves 86 . Smoking is additionally associated with high BP and CVD mortality 87,88 . While distinct evidence indicates that smoking and high BP affect the risk of death from CVD, the mixed impacts of these factors have rarely been examined. In Wold et al. study, It was indicated that systemic hypertension and vasoconstriction because of transient exposure to PM could increase the risk of acute heart failure. Besides, pulmonary and right ventricular diastolic pressures increment with PM exposure, showing the impact of pulmonary vasoconstriction on air pollution that can worsen congestive heart failure 89 . Evidence suggests that despite the undeniable impact of poor eating habits with extra calorie intake and low physical activity 90 , endocrine-disrupting chemicals (EDC) also intervene in insulin secretion to demonstrate the importance of exposure to environmental pollutants on the pathogenesis of diabetes 91,92 . Air pollution may impair insulin response sensitivity 76 . In addition to hypertension and diabetes, obesity and overweight can participate in the global burden of chronic diseases such as CVD. Low-level exposures to industrial air pollution can play and be considered an endocrine disruptor in the obesity epidemic 93 . Obese people with diabetes might be at greater risk for cardiovascular impacts of PM 2.5 exposure 7 .
Although not all studies confirm a positive correlation between exposure to AAP and the incidence of multifactorial diseases such as diabetes, hypertension, and obesity, public health outcomes indicate the potential risk of air pollution as a pervasive environmental risk factor for hypertension or diabetes 57 . However, the participatory role of these hemodynamic changes in expanding acute cardiovascular events associated with AAP is unclear 94,95 . Since the effect of these factors together on heart disease is not fully understood, laboratory studies seem to be useful to determine the mechanism of these effects.

Strengths and limitations.
Exposure to AAP is pervasive and occurs in a wide range. We were able to show this relationship to a large extent by considering other influential factors along with air pollution. In many cases, measuring the long-term exposure of each person to any of the air pollutant particles is very difficult and complex, and our use of an ecological study has been able to solve this problem to a large extent. This investigation inspected the relationship between AAP and CVD mortality, environmental exposure and risk factors for CVD (DM2, high BMI, high SBP, high LDL cholesterol), and the relationship between traditional risk factors and CVD prevalence mortality. www.nature.com/scientificreports/ However, we know about the limitations of our study. This study is ecological, and the ecological fallacy should not be ignored 96,97 . The results of our study are the result of one data set and may not be generalizable to all individuals. Outdoor pollution may be approximately similar for residents of an area. However, indoor pollution can be quite different depending on the lifestyle of the people and the different ventilation of the house from one person to another. The GBD Study expresses that indoor air pollution represents 3 million deaths worldwide and is the fourth-highest risk factor for all deaths 50 . In addition, the cumulative effects of air pollutants should not be ignored. It should not be forgotten that air pollutants are varied during different days and seasons due to the temperature divergence. Personal and occupational exposure to air pollutants in vulnerable populations, particularly people with diabetes, high blood cholesterol, and high BMI could be reduced via simple measures, comprising: • Preference for walking, cycling, and public transport over car or motorcycle, • Avoid walking and cycling on high-traffic streets, especially during busy hours, • Exercising in healthy environments such as parks and gardens, • Considering the limitation of outdoor times during very polluted periods, particularly for infants, the elderly, and those with cardiorespiratory issues.
It is worth mentioning, that aside from preventive actions comprising indoor air purifications, smoking restrictions, newly generated and low emission cars, environmental researchers, have suggested large-scale outdoor devices for purifying urban air 98 . Burning fossil fuels is not just a significant source of air pollution yet additionally an important source of greenhouse gases. This way, avoiding the utilization of fossil fuels derivatives will have significant advantages for human health in terms of energy production, both through air pollution exposure and climate change.

Conclusion
The present study investigated the relationship between exposure to ambient air pollution and CVD mortality and other risk factors for CVD mortality. Our study findings indicated a significant relationship between ambient air pollution, ambient PM pollution, ambient ozone, and CVD mortality. We showed the relationship between the exposure to AAP (PM, ozone, and total ambient air pollution, Separately) and each of the investigated traditional risk factors of CVD, including DM2, high SBP, high BMI, and high LDL cholesterol. There is strong evidence to support the mechanism of the relationship between AAP and CVD mortality. However, the level of indoor air pollution should not be ignored. Due to the widespread prevalence of air pollution exposure, political interventions to decrease environmental pollution, especially air pollution, can significantly affect CVD health for people. Air pollution should be one of the various significant modifiable risk factors in the prevention and organization of CVD in health and investigation priorities. Our study suggests that more research must be done on the ideal strategies for reducing AAP and the effects of these exposures on the incidence and mortality of CVD and other associated risk factors.

Data availability
All used raw data in this study are available at http:// www. healt hdata. org/. The datasets analysed during the current study are available from the corresponding author on reasonable request.